Immune Checkpoint Inhibition as Single Therapy for Synchronous Cancers Exhibiting Hypermutation: An IRRDC Study

摘要

Introduction: Most patients develop a single cancer in their lifetime. However, in individuals with cancer-predisposition syndromes, both metachronous and synchronous tumors can be observed. This poses a therapeutic challenge because of the lack of agents simultaneously efficacious for both tumors, and the intolerable toxicity of using multiple regimens at once. Therefore, synchronous cancers have poor outcome and are frequently lethal. Biallelic germline variants in the DNA mismatch-repair (MMR) genes (MLH1/MSH2/MSH6/PMS2) leading to inability to repair mutations during DNA replication are the highlight of the cancer-predisposing constitutional MMR-deficiency syndrome (CMMRD). Individuals with CMMRD develop early, aggressive, hypermutant cancers, with > 40 different tumor types described. As high tumor mutation burden (TMB) can predict response to immunotherapy, CMMRD cancers are attractive candidates for immune checkpoint inhibition (ICI), regardless of tissue of origin or cancer type. Here, we report that in CMMRD, the prevalence and impact of metachronous/synchronous cancers are extremely high. Since all synchronous cancers are hypermutant, immunotherapy can result in objective responses and improved survival.